Challenges and Innovations in Osteochondral Regeneration: Insights from Biology and Inputs from Bioengineering toward the Optimization of Tissue Engineering Strategies

Abstract

Due to the extremely high incidence of lesions and diseases in aging population, it is critical to put all efforts into developing a successful implant for osteochondral tissue regeneration. Many of the patients undergoing surgery present osteochondral fissure extending until the subchondral bone (corresponding to a IV grade according to the conventional radiographic classification by Berndt and Harty). Therefore, strategies for functional tissue regeneration should also aim at healing the subchondral bone and joint interface, besides hyaline cartilage. With the ambition of contributing to solving this problem, several research groups have been working intensively on the development of tailored implants that could promote that complex osteochondral regeneration. These implants may be manufactured through a wide variety of processes and use a wide variety of (bio)materials. This review aimed to examine the state of the art regarding the challenges, advantages, and drawbacks of the current strategies for osteochondral regeneration. One of the most promising approaches relies on the principles of additive manufacturing, where technologies are used that allow for the production of complex 3D structures with a high level of control, intended and predefined geometry, size, and interconnected pores, in a reproducible way. However, not all materials are suitable for these processes, and their features should be examined, targeting a successful regeneration.

Keywords: additive manufacturing; biomaterials; hyaline cartilage; regenerative medicine; subchondral bone; tissue engineering.

Figure 1

Structural view of the osteochondral boundary. The figure of the left represents a schematic view of the knee joint through a coronal section; the magnification on the right shows an ideal bone-cartilage interface at the femur condyle. Bone tissue is vascularized and houses a wide variety of cells, including perivascular mesenchymal stromal cells (MSCs) that provide mesodermal osteoprogenitors. Osteoblasts are involved in bone matrix deposition and new bone formation; once the process is complete, they rest entrapped within the mineralized matrix and undergo terminal differentiation into osteocytes. Multinucleated osteoclasts, deriving from the blood monocyte lineage, are involved in matrix remodeling, and hence macrophages remove organic matrix debris. The hyaline cartilage features exclusively differentiated chondrocytes, clustered in isogenous groups within ECM lacunae. The cartilage ECM is stratified into layers according to the different orientations of the collagen fibers: in the superficial zone, the fibers run parallel to the articular surface; in the transition zone, the fibers are randomly oriented; in the deep zone, the fibers are perpendicular to the articular surface. The cartilage layer is tightly attached to the bone through its calcified zone. The figure is based on illustrations available at, and modified from, “SMART, Servier Medical Art” (https://smart.servier.com/ (accessed on 4 February 2021)).